The Olive Baboon model of Zika Virus induced fetal brain injury

寨卡病毒（ZIKV）通过伊蚊属蚊子传播给人类。继2013/14年法属波利尼西亚以及随后的2015年巴西大规模暴发寨卡病毒感染后，世界卫生组织（世卫组织）基于寨卡病毒与出生时患有包括小头畸形和中枢神经系统病变在内的一系列神经损伤的婴儿之间的联系，于2016年2月发布了国际关注的突发公共卫生事件。由于小头畸形的破坏性后果以及在没有小头畸形的情况下对胎儿中枢神经系统可能产生亚临床但显著的影响，可能导致认知、行为和其他中枢神经系统障碍，因此靶向治疗胎儿中枢神经系统具有重要的意义和关注。橄榄狒狒（Papio anubis）在遗传、大脑发育、胎盘、大小和免疫学方面与人类相似，使狒狒成为研究妊娠期寨卡病毒感染的优秀转化模型。我们的研究团队有在狒狒身上感染黄病毒的经验，包括寨卡病毒。我们在神经生物学，母胎医学和生理学方面的专业知识补充了这一点，以实现我们的目标。俄克拉何马州狒狒研究资源为我们提供了所需数量的定时怀孕狒狒来完成我们的目标。我们的总体假设是，在妊娠的不同阶段（妊娠早期、中期或晚期）母体感染寨卡病毒会导致不同程度的胎儿中枢神经系统病理表型，其中妊娠早期感染最为严重。特异性目的1-分析170dG（~足月）的胎儿大脑，以确定在50,90和150dG（妊娠天）进行长时间寨卡病毒感染的影响。特异性目的2：分析妊娠早期（50dG）、中期（90dG）和晚期（150dG）接种后14d的胎儿大脑。我们还将评估孕妇和胎儿对寨卡病毒的免疫反应、炎症反应、病毒血症、胎儿生长和胎盘病理和功能（脐血流量），以将寨卡病毒感染时间和炎症反应程度与胎儿结局联系起来。这一发现将为相关的非人类灵长类动物提供有关寨卡病毒胎儿结局的重要数据。

Zika virus (ZIKV) is transmitted to humans via the Aedes genus of mosquito. Following massive outbreaks of ZIKV infections in French Polynesia in 2013/14 and subsequently in Brazil in 2015, the World Health Organization (WHO) issued a Public Health Emergency of International Concern (Feb, 2016) based on the link between ZIKV and infants born with a spectrum of neurological insults including microcephaly and CNS lesions. Targeting of the fetal CNS is of major significance and concern due to the devastating outcome of microcephaly and the potential for sub-clinical yet significant impacts on the fetal CNS in the absence of microcephaly that could result in cognitive, behavioral and other CNS disorders. The olive baboon's (Papio anubis) similarity to humans in terms of genetics, brain development, placentation, size and immunology makes the baboon an excellent translational model for studies on ZIKV infection during pregnancy. Our research team has flavivirus experience, including ZIKV, in baboons. We complement this with expertise in neurobiology, maternal-fetal medicine and physiology necessary to accomplish our aims. The Oklahoma Baboon Research Resource provides us access to the needed numbers of timed-pregnant baboons to complete our aims. Our overarching hypothesis is that maternal ZIKV infection at different stages of gestation (first, second or third trimester) will result in different degrees of fetal CNS pathological phenotypes, the most severe arising from early gestation infection. Specific Aim 1- Analyze the fetal brain at 170dG (~term) to determine the effect of prolonged ZIKV infection performed at 50, 90 and 150dG (days gestation). Specific Aim 2: Analyze the fetal brain at 14 d post inoculation at early (50dG), mid (90dG) and late (150dG) gestation. We will also assess the maternal and fetal immune, inflammatory responses, viremia, fetal growth and placental pathology and function (umbilical blood flow) in response to ZIKV to relate timing of ZIKV infection and degree of inflammatory response to fetal outcome. The findings will provide essential data in a relevant non-human primate on the fetal outcome of ZIKV.